Samples and data are analyzed from a longitudinal population study (1965 to 2007) that allows study of the risk factors and effects of diabetes mellitus. Risk factors for obesity, hypertension, and nephropathy are also studied, along with the relationships of these diseases to diabetes and their effects on development of vascular complications and mortality. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. The roles of obesity, serum insulin concentrations, impaired glucose regulation, occupational and leisure-time physical activity and diabetes in relatives are assessed. Findings on risk factors for diabetes are applied to a multicenter randomized clinical trial of prevention of type 2 diabetes that is currently in a long-term outcomes phase (the Diabetes Prevention Program Outcomes Study). Studies of the genetics of type 2 diabetes, obesity, and diabetes complications are described in other projects. Knowledge of diabetes risk factors coming from this and other studies led to the hypothesis that type 2 diabetes could be prevented or delayed in adults at high short-term risk. This hypothesis was confirmed in the Diabetes Prevention Program (DPP), a multicenter randomized clinical trial in which many of the participants and investigators in this project participated. We are now in a long-term follow-up phase, the Diabetes Prevention Program Outcomes Study (DPPOS), to assess long-term success with weight loss, reduction in the incidence of diabetes, and effects on diabetes complications. The DPPOS also began a genetics component to test whether genes with known or suspected effects on type 2 diabetes affected diabetes incidence in the DPP and interacted with study interventions. We sought to identify the physiological implications of genetic variation at the HLA-DRB1 region in full-heritage Pima Indians in Arizona. Single-nucleotide polymorphisms from the HLA region on chromosome 6p were tested for association with skeletal muscle mRNA expression of HLA-DRB1 and HLADRA, and with type 2 diabetes mellitus and prediabetic traits. The A allele at rs9268852, which tags HLA-DRB1*02 (1602), was associated both with higher HLA-DRB1 mRNA expression (n=133, p=4.2710&#8722;14) and decreased risk of type 2 diabetes (n=3,265, OR 0.723, p=0.002). Among persons with normal glucose tolerance (n=266) this allele was associated with a higher mean acute insulin response during an intravenous glucose tolerance test (p=0.005), higher mean 30 min insulin concentration during an oral glucose tolerance test (p=0.017) and higher body fat percentage (p=0.010). The polymorphism was not associated with HLA-DRA mRNA expression or insulin sensitivity. In conclusion, HLA-DRB1*02 is protective for type 2 diabetes, probably by enhancing self tolerance, thereby protecting against the autoimmune-mediated reduction of insulin secretion. Over 30 loci have been associated with risk of type 2 diabetes at genome-wide statistical significance. Genetic risk scores (GRSs) developed from these loci predict diabetes in the general population. In the Diabetes Prevention Program, we tested if a GRS based on an updated list of 34 type 2 diabetesassociated loci predicted progression to diabetes or regression toward normal glucose regulation (NGR) in the Diabetes Prevention Program (DPP). We genotyped 34 type 2 diabetesassociated variants in 2,843 DPP participants at high risk of type 2 diabetes from five ethnic groups representative of the U.S. population, who had been randomized to placebo, metformin, or lifestyle intervention. We built a GRS by weighting each risk allele by its reported effect size on type 2 diabetes risk and summing these values. We tested its ability to predict diabetes incidence or regression to NGR in models adjusted for age, sex, ethnicity, waist circumference, and treatment assignment. In multivariate-adjusted models, the GRS was significantly associated with increased risk of progression to diabetes (hazard ratio HR = 1.02 per risk allele 95% CI 1.001.05;P = 0.03) and a lower probability of regression to NGR (HR = 0.95 per risk allele 95% CI 0.930.98;P <0.0001). At baseline, a higher GRS was associated with a lower insulinogenic index (P <0.001), confirming an impairment in b-cell function. We detected no significant interaction between GRS and treatment, but the lifestyle intervention was effective in the highest quartile of GRS (P <0.0001). In conclusion, a high GRS is associated with increased risk of developing diabetes and lower probability of returning to NGR in high-risk individuals, but a lifestyle intervention attenuates this risk.